Evidence indicates that SLE is polygenic, and it has been speculated that individual mutated genes may contribute to specific features of the disease. IL-21 is a type I cytokine that plays important roles in the differentiation of B cells into plasma cells, in dendritic cell maturation, and in T cell responses. IL-21 is therefore an attractive candidate gene for SLE. Preliminary studies strongly suggest that IL-21 is polymorphic in patients with SLE. The hypothesis to test is that IL-21 polymorphisms are associated with functional consequences that increase the susceptibility to SLE. Two specific aims are proposed: 1) characterize the polymorphisms and haplotypes of IL-21 that cause SLE susceptibility, and 2) determine the functional consequences of IL-21 polymorphisms upon SLE susceptibility.